FDA

Valganciclovir Hydrochloride

Approved 4 Nov 2014OralTablet

The FDA lists this product in 18 strengths and forms.

Indications

Valganciclovir Tablets are a deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor indicated for: Adult Patients (1.1) Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk. Pediatric Patients (1.2) Prevention of CMV disease in kidney and heart transplant patients at high risk.

1.1Adult Patients Treatment of Cytomegalovirus (CMV)

Retinitis : Valganciclovir Tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [ see Clinical Studies (14.1) ]. Prevention of CMV Disease : Valganciclovir Tablets are indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [ see Clinical Studies (14.1) ].

1.2Pediatric Patients Prevention of CMV

Disease : Valganciclovir Tablets are indicated for the prevention of CMV disease in kidney transplant patients (4 months to 16 years of age) and heart transplant patients (1 month to 16 years of age) at high risk [ see Clinical Studies (14.2) ].

Contraindications

Valganciclovir is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions (6.1)]. Hypersensitivity to valganciclovir or ganciclovir. (4)

Warnings and precautions

Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function. (2.5, 5.2, 8.5, 8.6)

Indications

1.1Adult Patients Treatment of Cytomegalovirus (CMV)

1.2Pediatric Patients Prevention of CMV

Warnings and precautions

Interactions

In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for valganciclovir. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of valganciclovir and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug.

Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9. Table 9 Established and Other Potentially Significant Drug Interactions with Ganciclovir Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment Imipenem-cilastatin Unknown Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.

Cyclosporine or amphotericin B Unknown Monitor renal function when valganciclovir is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine [ see Warnings and Precautions (5.2) ]. Mycophenolate mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) Based on increased risk, patients should be monitored for hematological and renal toxicity.

Other drugs associated with myelosuppresion or nephrotoxicity (e.g., adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/ sulfamethoxazole, vinblastine, vincristine, and zidovudine) Unknown Because of potential for higher toxicity, coadministration with valganciclovir should be considered only if the potential benefits are judged to outweigh the risks. Didanosine ↔ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis) Probenecid ↑ Ganciclovir Valganciclovir dose may need to be reduced.

Monitor for evidence of ganciclovir toxicity. Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. (7) Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. (5.2, 7) Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased.

Monitor for ganciclovir and MMF toxicity. (7) Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider for concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks. (7) Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). (7) Probenecid: May increase ganciclovir levels.

Monitor for evidence of ganciclovir toxicity. (7) Double click here to open Word Application. Write ordered list in to word document. Close Word Application.

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, valganciclovir is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of valganciclovir or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and the risk of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.3) ]. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome.

However, in immunocompromised patients (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is a result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth.

Mortality in these infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.

Data Animal Data Doses resulting in two-times the human exposure of ganciclovir (based on the human AUC following a single intravenous infusion of 5 mg per kg of ganciclovir) resulted in maternal and embryo-fetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice. Rabbits showed increased embryo fetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs).

Increased embryo-fetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7 times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta.

The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL.

Adverse reactions

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hematologic Toxicity [ see Warnings and Precautions (5.1) ]. Acute Renal Failure [ see Warnings and Precautions (5.2) ]. Impairment of Fertility [ see Warnings and Precautions (5.3) ]. Fetal Toxicity [ see Warnings and Precautions (5.4) ]. Mutagenesis and Carcinogenesis [ see Warnings and Precautions (5.5) ]. The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with valganciclovir tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting.

The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with valganciclovir for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. Adult patients: Most common adverse reactions and laboratory abnormalities (reported in at least one indication by greater than or equal to 20% of patients) are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting.

(6.1) Pediatric patients: Most common adverse reactions and laboratory abnormalities (reported in greater than or equal to 20% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS contact Strides Pharma Inc. at 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse reactions known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir.

Adverse Reactions in Adults: Treatment of CMV Retinitis in AIDS Patients : In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse reactions reported by patients receiving valganciclovir tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), and headache (9%, 5%).

The incidence of adverse reactions was similar between the group who received valganciclovir tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving valganciclovir tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.

Adverse reactions and laboratory abnormalities are available for 370 patients who received maintenance therapy with valganciclovir tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received valganciclovir tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show pooled selected adverse reactions and abnormal laboratory values from these patients.

Table 3 Pooled Selected Adverse Reactions Reported in greater than or equal to 5% of Patients who Received Valganciclovir Tablets Maintenance Therapy for CMV Retinitis Patients with CMV Retinitis Adverse Reactions According to Body System Valganciclovir Tablets (N=370) % Gastrointestinal system Diarrhea 41 30 21 15 Nausea Vomiting Abdominal pain General disorders and administrative site conditions Pyrexia 31 Nervous system disorders Headache Insomnia Neuropathy peripheral Paresthesia 22 16 9 8 Eye disorders 15 Retinal detachment Table 4 Pooled Selected Laboratory Abnormalities Reported in Patients Who Received Valganciclovir Tablets Maintenance Therapy for the Treatment of CMV Retinitis Patients with CMV Retinitis Laboratory Abnormalities Valganciclovir Tablets (N=370) % Neutropenia: ANC/µL < 500 19 500 – < 750 17 750 – < 1000 17 Anemia: Hemoglobin g/dL < 6.5 7 6.5 – < 8.0 13 8.0 – < 9.5 16 Thrombocytopenia: Platelets/µL < 25000 4 25000 – < 50000 6 50000 – < 100000 22 Serum Creatinine: mg/dL > 2.5 3 > 1.5 – 2.5 12 Prevention of CMV Disease in Solid Organ Transplant Patients: Table 5 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received valganciclovir tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant.

The majority of the adverse reactions were of mild or moderate intensity. Table 5 Percentage of Selected Grades 1-4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients From a Study of Solid Organ Transplant Patients Adverse Reactions Valganciclovir Tablets (N=244) % Oral Ganciclovir (N=126) % Gastrointestinal disorders Diarrhea 30 29 Nausea 23 23 Vomiting 16 14 Nervous system disorders Tremors 28 25 Headache 22 27 Insomnia 20 16 General disorders and administration site conditions Pyrexia 13 14 Table 6 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from another clinical trial where kidney transplant patients received either valganciclovir once daily starting within 10 days post-transplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily until Day 200 post-transplant.

The overall safety profile of valganciclovir did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients. Table 6 Percentage of Selected Grades 1-4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients from a Study of Kidney Transplant Patients Adverse Reactions Valganciclovir Tablets Day 100 Post-transplant (N=164) % Valganciclovir Tablets Day 200 Post-transplant (N=156) % Gastrointestinal disorders Diarrhea 26 31 Nausea 11 11 Vomiting 3 6 Nervous system disorders Tremors 12 17 Headache 10 6 Insomnia 7 6 General disorders and administration site conditions Pyrexia 12 9 Table 7 and Table 8 show selected laboratory abnormalities reported with valganciclovir tablets in two trials in solid organ transplant patients.

Table 7 Selected Laboratory Abnormalities Reported in a Study of Adult Solid Organ Transplant Patients* *Laboratory abnormalities are those reported by investigators. Laboratory Abnormalities Valganciclovir Tablets (N=244) % Ganciclovir Capsules (N=126) % Neutropenia: ANC/µL < 500 5 3 5 3 2 2 500 - < 750 750 - < 1000 Anemia: Hemoglobin g/dL < 6.5 1 2 6.5 – < 8.0 5 31 7 25 8.0 – <

9.5Thrombocytopenia:

Platelets/µL < 25000 0 1 18 2 3 21 25000 – < 50000 50000 – < 100000 Serum Creatinine: mg/dL 14 45 > 2.5 21 47 > 1.5 –

2.5Table 8 Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant

Patients* *Laboratory abnormalities are those reported by investigators. Laboratory Abnormalities Valganciclovir Tablets Day 100 Post-transplant (N=164) % Valganciclovir Tablets Day 200 Post-transplant (N=156) % Neutropenia: ANC/µL 9 6 7 < 500 10 6 5 500 – < 750 750 – < 1000 Anemia: Hemoglobin g/dL < 6.5 0 5 17 1 1 15 6.5 – < 8.0 8.0 – <

9.5Thrombocytopenia:

Platelets/µL < 25000 0 1 7 0 0 3 25000 – < 50000 50000 – < 100000 Serum Creatinine: mg/dL > 2.5 17 50 14 48 > 1

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Valganciclovir Hydrochloride

Indications

1.1Adult Patients Treatment of Cytomegalovirus (CMV)

1.2Pediatric Patients Prevention of CMV

Contraindications

Warnings and precautions

Two medicines in one question?

Valganciclovir Hydrochloride

Indications

1.1Adult Patients Treatment of Cytomegalovirus (CMV)

1.2Pediatric Patients Prevention of CMV

Contraindications

Warnings and precautions

Two medicines in one question?

5.1Hematologic Toxicity

5.2Acute Renal Failure

5.3Impairment of Fertility Based

5.4Fetal Toxicity

5.5Mutagenesis and Carcinogenesis

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

9.5Thrombocytopenia:

2.5Table 8 Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant

9.5Thrombocytopenia:

Composition

Strengths and forms

Official product information

At a glance